In glomerulonephritis (GN), the changes that occur in the glomerulus including the degradation of the glomerular basement membrane (GBM) result in its increased permeability to proteins. This consequently develops into a condition known as proteinuria, the primary manifestation of GN. The mechanisms responsible for these changes are not known. The proposed study will elucidate this mechanism by examining the role played by cysteine proteinases (also called thiol proteases) in the disease. The proposed work is based upon the hypothesis that glomerular cysteine proteinases are involved in the injury process. Recent results obtained in the PI's lab and others have given support to this hypothesis by showing that 1) the glomerular cysteine proteinases, cathepsins B and L, degrade GBM in vitro, and 2) inhibitors of these proteinases ameliorate the disease in experimental animals. The proposed plan will elucidate the role played by cathepsins B and L and by a) comparing the activities of these enzymes in glomeruli, tubules, urines, and sera in normal versus nephrotic rats during various stages of the disease, and 2) testing exogenously administered inhibitors and activators of the enzymes for their effect on the disease by monitoring proteinuria, cysteine proteinase activities, and histological changes. Experiments will be done using two established models of GN in rats. Glomerular disease is the major cause of end-stage renal failure. An understanding of the mechanisms of glomerular injury is essential to the development of safer, more effective and newer forms of therapy. The successful completion of the work proposed here will provide information on the potential role of cysteine proteinases in GN, and will contribute to our understanding of tissue damage in general.